Abstract
Elucidating resistance mechanisms for therapeutic monoclonal antibodies (MAbs) is challenging, because they are difficult to study in non-human models. We therefore developed a strategy to genetically map in vitro drug sensitivity, identifying genes that alter responsiveness to rituximab, a therapeutic anti-CD20 MAb that provides significant benefit to patients with B-cell malignancies. We discovered novel loci with genome-wide mapping analyses and functionally validated one of these genes, CBLB, which causes rituximab resistance when knocked down in lymphoma cells. This study demonstrates the utility of genome-wide mapping to discover novel biological mechanisms of potential clinical advantage.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Antibodies, Monoclonal / administration & dosage
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Antibodies, Monoclonal / adverse effects
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Antibodies, Monoclonal / genetics
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Antigens, CD20 / drug effects
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Antigens, CD20 / immunology
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Antineoplastic Agents
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Cell Line, Tumor
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics*
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Genetic Linkage
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Genome, Human / genetics
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / complications
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Male
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Proto-Oncogene Proteins c-cbl / genetics*
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Rituximab / administration & dosage
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Rituximab / adverse effects*
Substances
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Adaptor Proteins, Signal Transducing
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Antibodies, Monoclonal
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Antigens, CD20
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Antineoplastic Agents
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Rituximab
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CBLB protein, human
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Proto-Oncogene Proteins c-cbl